There is growing interest in the use of inhaled nitric oxide (NO) to treat various conditions characterized by pulmonary hypertension or hypoxemia. Clinical use of inhaled NO began in the early 1990s. To date, inhaled NO has been administered primarily to critically ill, intubated, mechanically ventilated patients. Recently, it has become recognized that inhaled NO is also useful for treatment of spontaneously breathing patients such as cardiac surgery patients, organ transplant patients, and patients with pulmonary hypertension or sickle cell disease.
Systems for delivering inhaled NO to spontaneously breathing patients have been described (Wessel et al., 1994, Crit. Care. Med. 22:930). Inhaled NO has been delivered to spontaneously breathing patients through a nasal cannula (Yoshida et al., 1997, Am. J. Respir. Crit. Care Med. 155:526). In some cases, NO delivery through a nasal cannula has been pulsed delivery (Channick et al., 1996, Chest 109:1545).
In a normal human breathing pattern, about one third of the time consists of inspiration (inhalation), and about two thirds of the time consists of expiration (exhalation). Thus, in a continuous flow nasal cannula system, at least two thirds of the gas flowing from the source, e.g., a portable gas cylinder, is wasted. The basic concept of a pulsed dosage system is to deliver the therapeutic gas, e.g., oxygen or NO, only during the inspiratory phase of the breathing cycle.
By conserving gas, a pulsed dosage system reduces NO costs. It also increases the lifetime of an No source (gas cylinder), or decreases cylinder size. The latter two considerations are particularly important in home-care systems and portable systems for ambulatory patients. The mixture of NO and nitrogen administered from a nasal cannula system contains no moisture, and can cause discomfort from a drying effect on nasal membrane tissue. Thus, an additional benefit of a pulsed dosage system is reduced drying of nasal tissues. This increases patient comfort and improves patient compliance.
NO is an unstable, diatomic, highly lipophilic free radical. NO reacts rapidly with molecular oxygen (O.sub.2) to produce nitrogen dioxide (NO.sub.2), which is toxic at low levels. OSHA has set exposure limits for NO.sub.2 at 5 ppm. Animal studies have shown altered surfactant hysteresis and produced alveolar cell hyperplasia, changes in the epithelium of the terminal bronchiole, and loss of cilia at inhaled NO.sub.2 concentrations as low as 2 ppm (Evans et al., 1972, Arch. Environ. Health 24:180; Stephens et al., 1972, Arch. Environ. Health 24:160. In humans, 2.3 ppm NO.sub.2 has been shown to affect alveolar permeability (Rasmussen et al., 1992, Am. Rev. Respir. Dis. 146:654). Increased airway reactivity in humans has been found at inhaled NO.sub.2 concentrations below 2 ppm (Bylin et al., 1988, Eur. Respir. J. 1:606; Morrow et al., 1992, Am. Rev. Respir. Dis. 145:291; Stephens et al., supra).
NO is typically manufactured from the reaction of sulfur dioxide with nitric acid (Body et al., 1995, J. Cardiothorac. Vasc. Anesth. 9:748). Alternatively, it can be produced by reacting sodium nitrite and sulfuric acid (Young et al., 1996, Intensive Care Med. 22:77) or by the oxidation of ammonia over a platinum catalyst at high temperatures (Body et al., supra). Following its production, NO is mixed with nitrogen gas (N.sub.2) to obtain the desired NO concentration. The NO/N.sub.2 mixture is placed into specially prepared, aluminum alloy cylinders. For medical applications, cylinders typically contain 400 to 800 ppm NO (Hess et al., supra). In an NO cylinder, the NO.sub.2 concentration is normally less than 2% of the NO concentration.